ABSTRACT
Ten-Eleven-Translocation 2 (TET2) is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) and thereby alters the epigenetic state of DNA; somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies. To study the function of TET2 in vivo, we analyzed Ayu17-449 (TET2(trap)) mice, in which a gene trap insertion in intron 2 of TET2 reduces TET2 mRNA levels to about 20% of that found in wild-type (WT) mice. TET2(trap/trap) mice were born at Mendelian frequency but died at a high rate by postnatal day 3, indicating the essential role of TET2 for survival. Loss of TET2 results in an increase in the number of hematopoietic stem cells (HSCs)/progenitors in the fetal liver, and TET2(trap/trap) HSCs exhibit an increased self-renewal ability in vivo. In competitive transplantation assays, TET2(trap/trap) HSCs possess a competitive growth advantage over WT HSCs. These data indicate that TET2 has a critical role in survival and HSC homeostasis.
Subject(s)
DNA-Binding Proteins/physiology , Hematopoietic Stem Cells/physiology , Homeostasis , Proto-Oncogene Proteins/physiology , Animals , Cell Survival , Dioxygenases , Hematopoiesis , Hematopoietic Stem Cells/cytology , Janus Kinase 2/physiology , Mice , Mice, Inbred C57BL , RNA, Messenger/analysisSubject(s)
Bone Marrow/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Neoplastic Stem Cells/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Bone and Bones/metabolism , Bone and Bones/pathology , Cell Hypoxia/genetics , Cell Hypoxia/physiology , Cell Line, Tumor , Gene Expression Regulation, Leukemic , HL-60 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , K562 Cells , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Mice , Neoplasm, Residual/etiology , Neoplasm, Residual/genetics , Neoplasm, Residual/metabolism , Neoplastic Stem Cells/pathology , U937 Cells , Up-Regulation , Xenograft Model Antitumor AssaysABSTRACT
Janus kinase 1 (JAK1) and JAK3 plays a critical role in lymphocyte proliferation and differentiation. Somatic JAK1 mutations are found in 18% of adult precursor T acute lymphoblastic leukemias and somatic JAK3 mutations are found in 3.3% of cutaneous T cell lymphomas. Some of the mutations are confirmed as a gain-of-function mutation and are assumed to be involved in leukemogenesis. Adult T cell leukemia/lymphoma (ATLL) is a type of T cell neoplasm, and activation of JAK/STAT pathways is sometimes observed in them. We investigated JAK1 and JAK3 mutations in 20 ATLL patients. No JAK1 mutations were found, and five types of single nucleotide polymorphisms were observed in 12 cases, whose frequencies almost match those in Asian populations. As for JAK3, a synonymous mutation was found in one case. JAK1 and JAK3 mutations are unlikely involved in the leukemogenesis of ATLL.
Subject(s)
Janus Kinase 1/genetics , Janus Kinase 3/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Adult , Cell Differentiation , Cell Proliferation , DNA Mutational Analysis , Humans , Japan , Leukemia-Lymphoma, Adult T-Cell/etiology , Polymorphism, Single NucleotideABSTRACT
An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
Subject(s)
Gene Expression Regulation/physiology , Janus Kinase 2/genetics , Polycythemia Vera/genetics , Primary Myelofibrosis/genetics , Thrombocythemia, Essential/genetics , Animals , Bone Marrow Transplantation , Cytokines/metabolism , Female , Humans , Leukocytosis/pathology , Male , Megakaryocytes/cytology , Megakaryocytes/metabolism , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Mutation/genetics , Myeloid Cells/cytology , Myeloid Cells/metabolism , Phosphorylation , Polycythemia Vera/metabolism , Polycythemia Vera/pathology , Primary Myelofibrosis/metabolism , Primary Myelofibrosis/pathology , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/metabolism , STAT5 Transcription Factor/metabolism , Thrombocythemia, Essential/metabolism , Thrombocythemia, Essential/pathologyABSTRACT
The present paper reports 3 cases of aphasia with small lesions in the region of the basal ganglia to discuss whether neostrial dysfunction can cause aphasic symptoms. The Standard Language Tests of Aphasia (SLTA) was used to assess the type and degree of aphasia. Two patients with infarction either in the left putamen or in the head of the left caudate nucleus showed severe disturbance only in recalling words, especially nouns. The other patient showed the same symptom, in addition to writing disturbance that developed shortly after surgical extirpation of an arteriovenous malformation (AVM) in the left caudate nuclei. The symptoms common to the 3 patients corresponded well to the "anomic aphasia" proposed by Benson. The aphasic symptoms disappeared completely or largely within several months. This easy reversibility suggests that the aphasic disorder in the three patients was caused by damage not to the basal ganglia themselves, but to the affecting axons passing through or by the nuclei.
Subject(s)
Anomia/etiology , Basal Ganglia Diseases/complications , Aged , Brain/diagnostic imaging , Electroencephalography , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
In 152 patients who were suspected to have prostatic disease prostatic fluid obtained by a specially designed catheter was examined cytologically. Cytology was positive in 16 of 20 patients who initially were diagnosed clinically as having prostatic carcinoma, in 10 of 41 patients with suspected carcinoma and in 3 of 91 patients with clinical prostatic hypertrophy or other benign diseases. All but one of these cytologically positive cases finally were confirmed histologically to have prostatic carcinoma. In 4 patients initially diagnosed as having prostatic carcinoma cytology was not positive but in one the initial clinical diagnosis was incorrect and only 3 were false negative. This method of diagnosis is simple and highly effective in detecting prostatic carcinoma.
Subject(s)
Prostate/metabolism , Prostatic Neoplasms/diagnosis , Adenocarcinoma/diagnosis , Adult , Aged , Biopsy , Body Fluids/cytology , Catheterization/instrumentation , Cytodiagnosis , Humans , Male , Middle Aged , Prostate/pathology , Prostatic Hyperplasia/diagnosis , Prostatitis/diagnosisABSTRACT
Ureteral varices have been considered to be a relatively rare disease. Recently, reports on varices have been increasing with the development of X-ray examination, especially with the popularization of renal phlebography. We diagnosed left ureteral varices in 8 cases by renal venography. In 7 of these cases, gross hematuria was the main symptom, and varicocele accompanied it in the other case. In 7 cases of hematuria, surgery, ligation and removal of the varices was performed as palliative therapy for symptom; and, in all 7 cases, the gross hematuria disappeared in 7 to 18 months postoperatively. Ureteral varices should be classified into idiopathic and secondary types. In the case of idiopathic varices, a regional operation is sufficient to prevent venous reflux of the ureteral vein, and extensive surgery is needed in cases of collateral circulation on the venograms and secondary varices because of the unchangeable postoperative venous hypertension. We concluded that surgical treatment of ureteral varices is effective and is a useful palliative procedure in spite of the short postoperative follow up.